ABSTRACT Innovative treatment approaches are desperately needed for the 10.4 million new cases/year of Tuberculosis (TB). Up to 20% of these patients fail to complete antibiotic treatment, as it requires at least 6 months of multiple drugs with significant side effects. Incomplete treatment leads to disease with multi-drug resistant strains. Manipulating the host immune response to Mycobacterium tuberculosis (Mtb) represents an attractive alternative to antibiotics as only 5-10% of subjects with evidence of an immune response to TB will develop active TB disease. Yet, such efforts are stalled because Mtb sets up chronic infection within innate immune cells in the lung through manipulating their activation state and microbial killing pathways. Altered innate cell function delays arrival of activated T lymphocytes to the lung resulting in impaired Mtb killing. In this exploratory proposal, we propose to test a novel host-directed therapeutic (HDT) strategy for active TB. We do this via inhaled nanoparticles to mimic the effects of an immune danger signal targeted specifically toward Mtb- infected macrophages. In our preliminary studies, we found that Mtb infected macrophages increase their surface expression of the hyaluronic acid (HA) receptor CD44. Low molecular weight hyaluronan (LMWHA) acts as an endogenous danger signal and induces classical macrophage activation through its receptor CD44. Furthermore, it induces macrophages to secrete specific cytokines/chemokines, which facilitate T cell migration to the site of infection. In our initial studies, we conjugated silicone mesoporous nanovectors (SMP), with CD44-specific Thioaptamers (CD44TA) targeting CD44 (CD44TA-SMP). A single injection into Mtb infected mice caused greater than a log decrease in Mtb load. This was associated with selective entry of CD44TA-SMP into Mtb infected macrophages and induction of macrophage mediated Mtb killing. CD44TA-SMP treatment did not cause toxicities in uninfected cells and tissues. In response to reviewers' critiques, to achieve feasibility of use in point of care settings/ scale up needs, we propose using CD44TA conjugated to biocompatible and biodegradable phospholipid-based liposomes (CD44TA-LIP) via nebulized aerosol delivery given with or without anti-Mtb drugs. In this exploratory proposal, we want to determine the safety and efficacy of CD44TA-LIP in Mtb infected mice. Additionally, we expect to determine if CD44TA-LIP treatment induces LMWHA-specific immune responses outlined above to overcome Mtb infection. Specific Aims of this project are 1: To determine optimal dosage, biodistribution, efficacy and safety of inhaled CD44TA-LIP. 2: To assess the nature of the immune responses generated by short and long-term inhaled CD44TA-LIP on innate and adaptive cellular immunity against Mtb. Understanding how CD44TA-LIP enhance host immunity against the pathogen will be critical to using it as host-directed therapy in future large animal and phase I human studies to decrease treatment time and overall burden of tuberculosis.